The Mediterranean Zone (20 page)

Obviously, one key to this challenge was reducing the intake of the omega-6 fatty acid precursor (linoleic acid) that is necessary for AA formation. For much of human history linoleic acid was a minor part of the human diet. That changed eighty years ago with the industrialization of vegetable oil processing that, virtually overnight, produced a flood of omega-6 rich vegetable oils (corn, soybean, sunflower, and safflower). These soon became the most inexpensive form of calories known on the face of the earth. As a result, the levels of linoleic acid in the human diet began to rise, first in America and then spreading worldwide through the globalization of food. That situation might have been tolerable, since there were two rate-limiting steps that control the flow of linoleic acid into AA.

Both of the key regulatory enzymes (delta-6 and delta-5 desaturase) that control the ultimate formation of AA are activated by insulin and are inhibited by the omega-3 fatty acids (EPA and DHA). Unfortunately, just as linoleic acid levels were beginning to increase in the human diet, so were the levels of refined carbohydrates that enter the bloodstream very quickly as glucose (thus increasing insulin) coupled with a dramatic drop in the dietary intake of omega-3 fatty acids.

The hormonal response to any rapidly rising blood glucose is an increased secretion of insulin. When high levels of linoleic acid combine with high levels of insulin, the result is increased AA formation. It’s like adding a lighted match to a vat of gasoline. This is because insulin activates the key enzymes (delta-6 and delta-5 desaturases) needed to convert linoleic acid into AA. EPA and DHA can partially, but not totally, inhibit this metabolic consequence of the increased intakes of linoleic acid and refined
carbohydrates. Thus the key to really controlling AA formation is not only the restriction of omega-6 fatty acids, but also restriction of high-glycemic carbohydrates as described in
Chapter 3
.

The more you control the intake of omega-6 fatty acids and high-glycemic carbohydrates, the less omega-3 fatty acids you need to keep your inflammatory responses in a healthy zone. Of course, the converse is also true. The more omega-6 fatty acids and high-glycemic carbohydrates you consume, the more omega-3 fatty acids you need to control excess AA formation. Even following a strict Mediterranean Zone dietary program, there is usually a need to supplement the diet with omega-3 fatty acids either from high fish consumption or supplementation with highly purified omega-3 fatty acids to help slow down the formation of AA as well as increase the rate of resolution of the inflammatory response.

Just as omega-6 fatty acids drive inflammation, omega-3 fatty acids are the drivers of both anti-inflammation and pro-resolution. Well, some are. The most abundant omega-3 fatty acid is alpha-linolenic acid (ALA), which is found in high concentrations in certain seeds (flax and chia), leafy plants such as purslane, and nuts (walnuts being the highest). ALA has no anti-inflammatory properties unless it is transformed in the longer chain omega-3 fatty acids such as EPA and DHA. Unfortunately, this metabolic conversion is a very slow and inefficient process with only 1 and 5 percent of the ingested ALA becoming either DHA or EPA respectively. The oil found in fatty fish such as salmon, sardines, and anchovies, on the other hand, are rich in EPA and DHA. That is because they are at the end of the marine food chain that starts with algae, which make EPA and DHA readily. So if you want to gain the full anti-inflammatory and pro-resolution benefits of the Mediterranean Zone, plan to eat a lot of seafood. Until recently, fish was one of the main sources of protein in the Mediterranean diet before the high cost of fish and fears of toxins such as PCBs and mercury placed a real damper on this dietary practice. This is why purified omega-3 fatty acid supplements actually become a better choice than fish to enhance the benefits of the Mediterranean Zone.

EPA and DHA are quite different in their functions in the body. EPA is virtually identical to AA from a three-dimensional viewpoint. This is why
it can inhibit the formation of pro-inflammatory eicosanoids by occupying the same binding site as AA on the key enzymes necessary for the further metabolism into eicosanoids. DHA has a very different three-dimensional structure, making it much more difficult to compete with AA for those key binding sites of the COX enzyme. (COX enzymes are responsible for making both pro-inflammatory and anti-inflammatory prostaglandins.)

This is why the AA/EPA ratio is such an excellent marker for determining the extent of cellular inflammation. The higher the AA/EPA ratio, the easier it is to make inflammatory eicosanoids. The lower the AA/EPA ratio, the more difficult it is. So from this standpoint, EPA is more anti-inflammatory than DHA, at least in the initiation phase of inflammation.

Although DHA has a hard time fitting into the COX enzyme, it is a different story for the LOX enzymes. Both EPA and DHA can inhibit the formation of LOX-derived inflammatory eicosanoids such as leukotriene derived from AA as well as forming powerful pro-resolution resolvins coming from the same LOX enzymes. You need a very low AA/EPA ratio (between 1.5 and 3) to get the maximum resolution of inflammation because you have to saturate the EPA-binding sites of the more abundant COX enzymes first so that enough of the remaining EPA gets pushed over to the LOX pathways to make even more resolvins. That’s also why you always want a combination of EPA and DHA (with more EPA than DHA) to maximize the resolution of inflammation.

I believe the most appropriate AA/EPA ratio is that found in the longest-lived population in the world, the Japanese. The average AA/EPA ratio in the general Japanese population is about 1.5. For comparison, the average AA/EPA ratio in the American population is about 20. In older Italians (models for the Mediterranean diet), their AA/EPA was about 10 or about midway between the Americans and the Japanese. However, the AA/EPA ratio in the younger generation of Italians is rapidly increasing and is now equal to that of Americans, indicative of the impact of increasing consumption of both linoleic acid and refined carbohydrates through the globalization of industrialized foods as well as decreasing fish consumption.

There is also the constant need for DHA as well as EPA. DHA has such different structural properties compared to EPA, and it is more effective in creating greater fluidity in both membranes and lipoproteins. Fluidity is especially important in neural membranes that require a very flexible membrane surface to facilitate the transport of neurotransmitters to maintain
nerve signaling. In addition, DHA tends to break up “lipid rafts” composed of saturated lipids and cholesterol in membranes. This often prevents the signaling of metastatic mediators needed for cancer growth.

You find EPA and DHA in every organ in the body to be relatively similar to their levels in the blood except in the brain, where the levels of EPA are negligible. This has led to a mistaken belief that EPA is not important for neural function, but nothing could be further from the truth. The brain is unique in that, unlike other organs in the body, the brain can’t effectively make AA, EPA, or DHA from shorter chain omega-3 or omega-6 fatty acids. The vast majority of these longer-chain essential fatty acids have to be transported across the blood-brain barrier. The transport efficacy of all three is about the same, so the initial uptake of these fatty acids into the brain is roughly similar to their concentrations in the blood. However, once inside the brain, only the EPA is rapidly oxidized, whereas both AA and DHA are shuttled to long-term storage in the phospholipids of the neural membranes. Considering that EPA is critically important in every other organ as an anti-inflammatory compound, this seems to make no sense unless it is being oxidized into something that is even more important to the brain. I believe this is the case. The brain is extraordinarily sensitive to inflammatory damage. Therefore, it makes sense to oxidize the incoming EPA into resolvins, which act as constant anti-inflammatory sentinels to keep inflammation under control in the brain. However, resolvins have a very short lifespan, which means the supply of EPA to the brain must be constantly renewed. As a result, when you do a post-mortem analysis of the brain to look for EPA, it simply isn’t there compared to the longer-lived AA and DHA present in the phospholipids of the brain. It is the ultimate disappearing act in nature.

Five hundred million years ago, the only life forms on the planet were single-celled organisms. The explosion of biological diversity that created multi-cellular organisms required a new form of communication to allow cells with different functions to communicate within this more complex organism. That communication system was based on hormones, which acted as messengers in the early beginnings of the biological Internet. Eicosanoids were the first hormones developed by living organisms; they
had to do a lot of multi-tasking in the early days of the first multi-celled organisms. That’s why eicosanoids remain at the apex of the hormonal control mechanisms that directly or indirectly control all other hormonal actions in the body.

As with any good control system, you need an effective system of checks and balances. That’s why there are “good” eicosanoids and “bad” eicosanoids. These hormones are not good or bad in the absolute sense but simply have powerful yet opposing biological actions. Relative to inflammation, bad eicosanoids initiate (or turn on) inflammatory responses, and good eicosanoids resolve (that is, turn off) inflammatory responses. As long as these are balanced, the body’s inflammatory responses can respond to microbial attack or physical injuries quickly and will also bring the inflammatory response back to homeostasis as rapidly as possible.

The enzymes that convert omega-6 and omega-3 fatty acids into eicosanoids are diverse. Two of these—COX and LOX enzymes—have already been mentioned. But this is only a small number of the enzymes available to generate a wide number of different eicosanoids. The key factor is that both omega-6 and omega-3 fatty acids compete for these same enzymes. It is like a biological lottery: If you have the correct balance of these essential fatty acids in the cell, you win as the cell’s inflammatory response is in balance. If you have an excess of omega-6 to omega-3 fatty acids in the cell, then you run the risk of chronic low-level inflammation that leads to obesity, chronic disease, and the acceleration of the aging process.

You might think that the most primitive part of our immune system would be the simplest to figure out. After all, it is very similar to the immune system in plants. It turns out such thinking is wrong. Although the innate immune system is ancient, it is also very complex. That’s why the 2011 Nobel Prize in Medicine was awarded for earlier discoveries that began to unlock its sophisticated control mechanisms for maintaining an appropriate inflammatory response.

The innate immune system is relatively non-specific because it recognizes fragments of invading microbes that are taken as signals that the cell may be under attack. Once a microbial fragment is recognized, a complex series of signaling reactions take place that result in the release of a wide
variety of inflammatory proteins. These inflammatory proteins can either be new inflammatory signaling proteins (cytokines such as TNF, IL-1, and IL-6) that interact with nearby cells to stimulate their inflammatory responses or increased synthesis of inflammatory enzymes (COX-2) that can convert AA into pro-inflammatory eicosanoids that can transmit and amplify the inflammatory response to nearby cells.

Usually the first step in the process is the recognition of the fragments by sensors on the surface of the cell, known as toll-like receptors. (They were first discovered in fruit flies, as their absence made the fruit flies look weird. The German word for weird is
toll
). If you have a leaky gut, then you have a high likelihood of bacteria or bacteria fragments leaking into the blood. The toll-like receptors recognize these fragments as an indication you are under microbial attack and initiate the release of powerful inflammatory responses via the innate immune system. Unfortunately, these biological sentinels aren’t very discriminating, and as a result, food molecules can also interact with them. As an example, toll-like receptor 4 (TLR-4) recognizes a saturated fatty acid component of the bacterial wall. Dietary saturated fats can also bind to this same TLR-4 sensor and induce an inflammatory response.

The next step in the process is the interaction of the signals coming from activated toll-like receptors with specialized proteins inside the cell known as gene transcription factors, also found in every cell. These are the key players that turn on and turn off gene expression. The two most important from the standpoint of cellular inflammation are nuclear factor kappaB (NF-κB) and peroxisomal proliferator activator gamma (PPAR-γ). NF-κB is the genetic master switch that turns on inflammation, while PPAR-γ turns off the generation of inflammation by inhibiting NF-κB. Anything (including food components, such as saturated fats) that activates toll-like receptors will activate NF-κB. Likewise, anything (including food components such as omega-3 fatty acids and polyphenols) that activates PPAR-γ will reduce inflammation. However, the most powerful activator of NF-κB is stimulated by a group of inflammatory eicosanoids (leukotrienes and hydroxylated fatty acids such as 12-HETE) derived from AA. The more you lower AA in your cell membranes as well as increase the levels of EPA and DHA, the less likely you are to activate NF-κB. You reduce the levels of AA and saturated fat by following the Mediterranean
Zone. You increase EPA and DHA by eating a lot of fatty fish or taking purified omega-3 fatty acid supplements.

Another activator of NF-κB is oxidative stress, usually the consequence of excess free radical production. Excess glucose in the blood is a significant driver of oxidative stress because it is so chemically reactive. This is why excess carbohydrates as well as excess omega-6 and saturated fats are dietary factors that increase cellular inflammation.